1-substituted 1,2,3,4-tetrahydroxanthen-9-ones

ABSTRACT

This invention is concerned with 1-substituted 1,2,3,4tetrahydroxanthen-9-ones of type I,   wherein X is hydroxy or carbonyl oxygen, R1 and R2 are hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, or R1 and R2 taken together forming another ring such as benzene. These compounds are useful in allergic conditions such as bronchial asthma.

United States Patent [191 Klutchko et al.

[4 1 Jan. 21, 1975 I 1 l-SUBSTITUTEI) l,2.3,4-TETRAHYDROXANTHEN-Q-ONES[75] lnventors: Sylvester Klutchko, Hackettstown;

Maximilian Von Strandtmann,

Rockaway; John Shavel, Jr., Mendham. all of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: Aug. 23, 1973 [211 App] No.: 390,961

[52] US. Cl. 260/335, 424/283 [51] Int. Cl C07d 7/44 [58] Field ofSearch 260/335 [56] References Cited FOREIGN PATENTS OR APPLICATIONS8,546 5/1965 Japan Primary E.\mniner-Norma S. Milestone Attorney, Agent,or l*irrnAlhcrt H. Graddis; Frank S. Chow [57] ABSTRACT This inventionis concerned with l-substituted l,2',3,4- tetrahydroxanthen-9-ones oftype I.

9 Claims, No Drawings l -SUBST1TUTEI) 1.2.3 .4-TETRAHYDROXANTHEN-9-ONESThis invention is concerned with l-substituted 1.2.3.-4-tetrahydroxantltemQ-ottes of type 1.

Rl I Jones Reagens Acetone wherein X is hydroxy or carbonyl oxygen, R,and R are hydrogen. halogen. lower alkyl, lower alkoxy or hydroxy. or Rand R taken together forming another ring such as'benzenc.

These compounds are useful in allergic conditions such as bronchialasthma. Thus. the compounds of this invention are active orallyor i.p.in the prevention of allergic and asthmatic reactions in rats at doselevels of 100-150 mg/kg. For example. compound 1 wherein R is hydrogen.R is 5-isopropy1 and X is hydroxy shows a 54% inhibition of the allergicresponse at 100 mg/Kg when tested in the passive cutaneous anaphalaxis(PCA) screen, which is a modification of procedures described by l.Mota, Life Sciences. 7, 465 (1963) and Z. Ovary, O. Bier. Proc. Soc.Exprl. Biol. Med, 81. 585 (1952). 1

Consequently these compounds are indicated in the management of allergicconditions such as bronchial asthma. and hay fever.

Generally speaking. an oral dose of 100150 mg/kg two or three timesdaily is suggested. This regimen may be varied depending on the severityof the condition, the age, weight, sex of the host being treated.

In addition to the above pharmacological activity, the compounds of thisinvention also exhibit gastric antiulcer activity at a dose of -100mg/Kg in experimental animals such as rats. For example, when a compoundof type 1 wherein R, and R are hydrogen and X is hydroxyl is testedaccording to the procedure according to H. Shay. et. al..Gastmcntcrolugy, 5, 43 (1945), in the pylorus ligated rat. at a dose ofmg/Kg i.p., it caused a reduction of 52.2% in volume of gastric acid anda 31.571 reduction in the hydrogen ion concentration compared controls.

The compounds are administered in dosage forms suitable for human andveterinary usages. They include for example tablets, capsules, andinjections which are formulated by methods known to the pharmacists art.

According to one aspect of this invention, when X is lt-ydroxy thesecompounds are prepared from o-hydroxy-w-(mcthylsulfinyl) acetophenones11, which are prepared in accordance with the disclosure in U.S. Pat.No. 3.801.644 issued Apr. 2. 1974.

The conversion is carried out according to the fol lowing scheme:

OS-O H Referring to the above scheme. compound 11 is cyclized withglut-arie dialdehyde in the presence ofa base catalyst such aspiperidine at mild temperatures such as 50-80 C. The intermediate 111which may or may not be isolated is then converted to l. wherein X ishydroxy. by thermal elimination of the elements of CH,-,SOH at 1 10 to140 C.

The compounds of this invention 1 where X is carbonyl oxygen areprepared by oxidation of compounds I wherein X is hydroxy. preferablyusing the Jones reagent in acetone according to the following scheme:

To further illustrate the practice ofthis invention the followingexamples are included. Temperatures referred to hereinafter are indegrees Centigrade.

EXAMPLE I 1,2,3,4-Tetrahydro-1-hydroxy-5-methoxyxanthen- 9-one. Amixture of 22.8 g (0.1 mol) of 2-hydroxy-3-methoxy-2-(methylsulfinyl)-acetophenone, 40g (0.1

mol) of25% aqueous glutaric dialdehyde. ml of'dimethylformamide and 2'mlof piperidine was heated with stirring. At 50 C all solid went intosolution. At -1 15 the volatiles were distilled off. After /2 hour thetemperature was and the volume was about one halfofthe original volume.Most of the remaining dimethylformamide was removed at reduced pressure.The remaining viscous material, which became partly crystalline onstanding several days. was triturated with 50 ml of ethyl acetate,filtered and the filter cake was washed efficiently with 25 ml of ethylacetate; wt. 13.5 g (55% mp 136l38 Recrystallization from the ethylacetate gave pure product; mp 138-140.

Anal. Calcd for C H O C, 68.28; H, 5.73. Found: 1

EXAMPLE 2 EXAMPLE 3 1,2,3.4Tetrahydro-1-hydroxy-5-isopropylxanthen-9-one A mixture of 60 g (0.25 mol) of 2'-hydroxy-3- Iisopropyl-2-(methylsulfinyl-acetophenone, 100 g (0.25 mol) of 2571glutaric dialdehyde. 300 ml of dimethylformamide and 2 ml of piperidinewas reacted under the same conditions described for the preparation of l.2.3,4-tctrahydrol -hydroxy-S-methoxyxanthen- 9-one to give 24 g (37%)of product melting at lllll3. Recrystallization from ethyl acetate gavepure, cream colored material; mp l l4l 16.

Anal. Calcd for C H Q-p C, 74.39; H, 7.02. Found: C. 74.35; H, 7.l4.

EXAMPLE 4 7-Chlorol .2,3,4-tetrahydrol -hydroxyxanthen-9-one A mixtureof 58.l5 g (0.25 mol) of 5'-chloro-2-hydroxy-2-(methylsulfinyl)-acetophenone. I g (0.25 l

mol) of 25% glutaric dialdehyde. 300 ml of dimethylformamide and 2 ml ofpiperidine was reacted under the same conditions described for thepreparation of l,2,3,4-tetrahydrol -hydroxy--methoxyxanthen- 9-one togive 14.0 g (23%) of product melting at l44l46. Recrystallization fromethyl acetate gave pure, tan colored crystals; mp l45l47.

Anal. Calcd for C H Clo C,62.29; H, 4.42. Found: C, 62.24; H, 4.42.

EXAMPLE 5 8.9,l0,l l-Tetrahydro-8-hydroxy-7H-benzo[clxanthen- 7-onePreparation of intermediatehexahydro-8-hydroxy-7a-(methylsulfinyl)-7H-benzo[c]xanthen-7-one.

A stirred mixture of 24.8 g (0.1 mol) of 1-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone, 400 ml of methanol, 40.0 g (0.1mol) of 25% glutaric dialdehyde and 1 ml of piperidine was heated atreflux for 1 hour. Water (500 ml) was added to the solution toprecipitate a viscous material which partly crystallized. Thesupernatant was decanted, the residue was triturated with I00 ml ofwater and the mixture was filtered. The dried filter cake was heatedwith 30 ml of ahs. ethanol to 70 and the mixture was stirred for 5 min.,cooled. filtered and the filter cake washed with cold ethanol; wt.l().() g: mp l55-l58. Recrystallization from ethanol gave broad meltingcrystals; mp l60-l63, which apparently consists of isomers.

Anal. Calcd for C ,,H ,.O S:C,65.43; H. 5.49; 5,9.78. Found: C, 65.39;H. 5,64; S. 9.66.

Elimination Reaction on Intermediate Methylsulfinyl Derivative A mixtureof 10.0 g (0.03 mol) of 7a,8,9,10,l l,l lahexahydro-8-hydr0xy-7a-(methylsulfinyl )-7H-benzo[c]xanthen-7-one and 100 ml of xylene washeated at reflux for 5 minutes. The resulting solution yielded crystalson cooling; wt. 6.9 g (85% mp l75-l 78. Recrystallization fromZ-propanol gave pure 8,9,l0,lltetrahydro-8-hydroxy-7H-benzolc-lxanthen-7-one; mp l77l80.

Anal. Calcd for C H O C, 76.67; H, 5.30. Found: C. 76.79; H, 5.36.

EXAMPLE6 l.2.3.4-Tetrahydro-5-methoxyxanthen-l ,9-dione A solution of3.85 g (0.035 mol) olchromium trioxidc 1071 excess). 25 ml of water and3.l ml of cone. sulfuric acid was added over a 5 minute period to astirred solution of 12.3 g (0.05 mol) of l,2,3.4- tetrahydro-l-hydroxy-5-methoxyxanthen-9-one in [.800 ml of acetone. A greenish,linely divided solid separated. The mixture was stirred overnight andliltered. Both the filter cake and the filtrate contained product andwere worked up. The filter cake, apparently containing a chromiumcomplex of the diketone, was dissolved in 75 ml of water and heated at80 on the steam bath for 10 minutes to destroy the complex. Theseparated crude solid was filtered, washed well with water and dried;wt. 4.0 g; mp 200230. The acetone filtrate was concentrated and theresidue was treated with 300 ml water to give another 2.l g of crudeproduct; mp l90220. Total wt. of crude was 6.1 g (50% Purification waseffected by dissolution in hot chloroform, filtration to removeinsolubles and addition of ethyl acetate. The pure crystal, thusobtained, melted at 236238.

Anal. Calcd for C, H O :C. 68.85; H. 4.95. Found: C, 68.61; H. 5.07.

EXAMPLE 7 l.2,3,4.-Tetrahydroxanthen-l .9-dione This compound wasprepared using the same reaction and work up conditions as in thepreparation of l-.-. 2,3,4-tetrahydro-S-methoxyxanthen-l,9-dione. Thequantities used were 11.88 g (0.055 mol) of l.2.3.4-tetrahydro-l-hydroxy-xanthen-9-one in 1800 ml of acetone with a solutionof 4.24 g (0.039 mol) of CrO (10% excess), 28 ml of water and 3.4 ml ofcone. H 50 The purified product weighed 2.7 g (23%) and melted at21l-2l3. Recrystallization from chloroform-ethyl acetate gave pureproduct; mp 2l2-2l3.

Anal. Calcd for C H O C, 72.89; H, 4.7l. Found: C. 72.87; H, 4.65.

EXAMPLE 8 7-Chlorol ,2,3,4-tetrahydroxanthenl ,9-dione This compound wasprepared using the same reaction and work up conditions as in thepreparation of l.- 2,3,4-tetrahydro-S-methoxyxanthen-l ,9-dione. The

- quantities used were 12.5 g (0.05 mol) of 7-chloroand wherein X ishydroxy or carbonyl oxygen. and R is hydrogen, halogen, lower alkyl orlower alkoxy.

2. A compound according to claim 1 which is l.2,3,4-Tetrahydro-l-hydroxy-S-methoxyxanthem9-one.

7. A compound according to claim 1 which is 1.23.4- Tetrahydro5-mcthoxyxanthcn l ,9-dionc.

8. A compound according to claim I which is l,2,3,4-Tctrahydroxanthcn-l,9-dionc.

9. A compound according to claim I which is 7- Chlorol,2,3,4-tctrahydroxanthenl ,9-dione.

1. A COMPOUND OF THE FORMULA WHEREIN X IS HYDROXY OR CARBONYL OXYGEN,AND R1 IS HYDROGEN, HALOGEN, LOWER ALKYL OR LOWER ALKOXY.
 2. A compoundaccording to claim 1 which is1,2,3,4-Tetrahydro-1-hydroxy-5-methoxyxanthen-9-one.
 3. A compoundaccording to claim 1 which is 1,2,3,4-Tetrahydro-1-hydroxyxanthen-9-one.4. A compound according to claim 1 which is1,2,3,4-Tetrahydro-1-hydroxy-5-isopropylxanthen-9-one.
 5. A compoundaccording to claim 1 which is7-Chloro-1,2,3,4-tetrahydro-1-hydroxyxanthen-9-one.
 6. A compoundaccording to claim 1 which is8,9,10,11-Tetrahydro-8-hydroxy-7H-benzo(c)xanthen-7-one.
 7. A compoundaccording to claim 1 which is1,2,3,4-Tetrahydro-5-methoxyxanthen-1,9-dione.
 8. A compound accordingto claim 1 which is 1,2,3,4-Tetrahydroxanthen-1, 9-dione.
 9. A compoundaccording to claim 1 which is7-Chloro-1,2,3,4-tetrahydroxanthen-1,9-dione.